Project 1 Summary Hepatitis C Virus (HCV) infection and type 2 diabetes mellitus (T2DM) are two major health concerns that are causing profound health disparities for underserved communities, particularly African-Americans (AA) who, as a group, suffer the highest rates of both diseases in the U.S. Our overall objective is to identify candidate genes and genetic pathways associated with the combination of T2DM and HCV. The rationale behind the study is informed by an emerging body of evidence supporting the hypothesis that HCV infection worsens the metabolic and insulin resistance abnormalities of diabetic patients, leading to even more unfavorable health outcomes. We propose to test this hypothesis by identifying the genes and genetic pathways perturbed by coexistence of the two diseases, in comparison to T2DM patients free of HCV. Our unique resource setting and collaboration provides an unmatched opportunity for examining these questions. Specific Aim 1 is to enroll a clinical population of subjects with T2DM in AA persons residing in the Washington, DC region: one group with HCV and one group without it. We will apply a gene expression analysis (microarray coupled with IPA analysis) to divulge the differential gene expressions and their pathways in those two groups. Global gene expression will be assessed in circulating white blood cells through microarray assays. Specific Aim 2 is to validate the candidate disease markers by applying highthroughput TaqMan Low Density Arrays (TLDA). We will validate the precise panel of genes within the particular biological pathways, and we will integrate clinical, epidemiologic and laboratory data to identify the robustness of these markers towards stability, validity, reproducibility, feasibility and utility of this new TLDA approach. The overreaching goal of this research is, therefore, to shed new light on possible mechanisms by which HCV may contribute to the disease burden of patients with T2DM, and identify avenues for treatment and prevention, for this minority population. The overreaching goal of this research is to shed new light on possible mechanisms by which HCV may contribute to the disease burden of T2DM, beyond that attributable to diabetes alone, and identify potential avenues for treatment and prevention in the African-American population, thereby contributing positively to the mission of HU RCMI to address minority health disparities.